Barrett's esophagus is the precursor of most esophageal adenocarcinomas and a large proportion of esophagogastric junctional adenocarcinomas. These diseases are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophgeal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett's esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett's esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Our research has characterized familial aggregation of Barrett's esophagus and its associated cancers, which we term Familial Barrett's Esophagus (FBE). We have developed a network of investigators who are actively identifying and accruing FBE families and biobanking lymphoblastoid cell lines in a centralized biorepository. Furthermore, our segregation analysis of pedigrees accrued to date indicates that FBE is the manifestation of autosomal dominant susceptibility alleles. Our central hypothesis: FBE has a genetic basis will now be tested in translational experiments designed to result in gene discovery. The specific aims of this proposal are: 1) to identify genomic loci linked to FBE trait in 46 multiplex multi-generational families already collected; 2) to narrow identified linkage regions in the larger cohort of all FBE families; and 3) to sequence genes of interest. Using the multidisciplinary approach of our collaborative team of investigators, these studies will result in novel information that explains the biological basis of FBE. Identification of genetic risk factors would lead to more effective screening programs and an improved understanding of the molecular pathogenesis of cancer.